Role of CD8IL-13 T cells in Chlamydia infection-associated immunopathology

描述(申请人提供)：尽管美国和欧洲进行了公共卫生努力和有效的抗生素治疗，但沙眼衣原体生殖道感染在美国和欧洲的青少年/年轻人中的流行率仍为2%-15%。人们普遍认为，接种疫苗对于降低其流行率是必要的。早期的沙眼衣原体(眼睛感染)疫苗保护效果不佳，加剧了免疫病理。开发安全的衣原体疫苗的关键是更好地了解免疫病理学。目前尚无实用的衣原体免疫病理学生物标志物。在沙眼衣原体小鼠模型中，其他研究人员已经清楚地表明，衣原体特异性CD8T细胞是免疫病理和不孕症的重要介体。我们最近发现，来自自我清除小鼠生殖道感染的衣原体特异性CD8T细胞克隆的一部分产生了导致瘢痕的细胞因子IL-10、肿瘤坏死因子�和IL-13。这些CD8克隆不受MHC Ia类分子的限制。类似的非Ia类限制性CD8 T细胞克隆也来自沙眼衣原体生殖道感染患者的外周血。利用基因表达芯片分析，我们已经确定了CD8IL-13T细胞的分子指纹。根据现有的小鼠和人类衣原体文献，明确了对衣原体生殖道感染的细胞免疫反应包括非Ia类限制性CD8T细胞。小鼠模型明确显示CD8 T细胞是免疫病理和不孕症的中介细胞。我们推测CD8免疫病理的机制是分泌IL-10、肿瘤坏死因子�和IL-13的非MHCIa限制性CD8T亚群。为了验证这一假设并调查潜在的免疫生物学，我们提出了以下特定目标：特殊目标#1-利用过继转移研究CD8IL-13T细胞在免疫病理学中的作用。我们有具有代表性的传统衣原体特异性CD8T细胞克隆，衣原体特异性CD8IL-13T细胞克隆，以及可能用于从免疫脾细胞或大量T细胞群中纯化CD8IL-13T细胞的细胞表面生物标志物。具体目的#2-研究衣原体特异性CD8IL-13T细胞的激活途径和其他免疫生物学特性。利用现有的T细胞克隆和基因表达微阵列分析，我们将比较激活的传统CD8和激活的CD8IL-13T细胞，以确定CD8IL-13的特异性免疫生物学；潜在地识别更多的生物标记物和治疗干预的靶点。我们将绘制衣原体特异性CD8T细胞克隆小组的表位来源蛋白图。具体目标#3-对人类CD8IL-13T细胞进行初步研究。利用小鼠模型中识别的CD8IL-13 T细胞亚群的假定生物标志物，我们将从健康人的外周血中分离CD8 T细胞，并确定人类中是否存在类似的CD8IL-13 T细胞亚群。

DESCRIPTION (provided by applicant): Chlamydia trachomatis genital tract infections have a prevalence of 2-15% in adolescents/young adults in the USA and Europe in spite of public health efforts and effective antibiotic therapy. It is widely accepted that a vaccine is necessary reduce its prevalence. An early C.trachomatis trachoma (eye infection) vaccine delivered poor protection and exacerbated immunopathology. Critical to developing a safe Chlamydia vaccine is a better understanding of immunopathology. Currently there are no practicable biomarkers for Chlamydia immunopathology. In the C. muridarum mouse model others have clearly shown that Chlamydia-specific CD8 T cells are important mediators of immunopathology and infertility. We have recently shown that a subset of Chlamydia-specific CD8 T cell clones derived from mice that self-cleared C. muridarum genital tract infections produce the scar-ogenic cytokines IL-10, TNF�nd IL-13. These CD8 clones are not restricted by MHC class Ia molecules. Similar non-class Ia restricted CD8 T cell clones have been derived from the peripheral blood of humans with C. trachomatis genital tract infections. Using gene expression microarray analysis we have identified a molecular fingerprint for CD8IL-13 T cells. Based on the existing mouse and human Chlamydia literature it clear that the cellular immune response to Chlamydia genital tract infections includes non-class Ia restricted CD8 T cells. The C. muridarum mouse model has unequivocally shown CD8 T cells to be mediators of immunopathology and infertility. We hypothesize that the mechanism underlying CD8 immunopathology is a non-MHC class Ia restricted CD8 T subset secreting IL-10, TNF�and IL-13. To test that hypothesis and investigate the underlying immunobiology we propose the following specific aims: Specific aim #1- to investigate the role of CD8IL-13 T cells in immunopathology utilizing adoptive transfer. We have representative conventional Chlamydia-specific CD8 T cell clones, Chlamydia-specific CD8IL-13 T cell clones, and putative cell surface biomarkers for purifying CD8IL-13 T cells from immune splenocytes or bulk T cell populations. Specific aim #2- to investigate the activation pathway and other immunobiology specific to Chlamydia-specific CD8IL-13 T cells. Utilizing existing T cell clones and gene expression microarray analysis we will compare activated conventional CD8 with activated CD8IL-13 T cells to identify CD8IL-13 specific immunobiology; potentially identifying additional biomarkers and targets for therapeutic intervention. We will als map the epitope source proteins for the Chlamydia-specific CD8 T cell clone panel. Specific aim #3- perform a preliminary investigation of CD8IL-13 T cells in humans. Using putative biomarkers for the CD8IL-13 T cell subset identified in the mouse model we will isolate CD8 T cells from the peripheral blood of healthy individuals and determine whether a similar CD8IL-13 T cell subset exists in humans.